Mechanisms of plasmid copy number control in bacterial pathogenesis and antibiotic resistance

Plasmids often encode virulence determinants and multi-antibiotic resistance.

Previously, we established that up-regulation of plasmid copy number (PCN) is an essential virulence mechanism in pathogenic Yersinia.

This regulatory tactic is most likely widespread amongst plasmid-carrying bacteria, enabling rapid adjustments of plasmid-encoded functions in response to environmental cues.

Using an extensive collection of clinical isolates, we have shown that gene dosage increases through PCN is a prevalent and general mechanism for generating transient antibiotic resistance.

Importantly, the high instability and fitness costs associated with increased PCN lead to a rapid reversion to antibiotic susceptibility without antibiotics, a phenomenon largely overlooked in clinical settings.

This project aims to elucidate the molecular mechanisms underlying PCN control in bacterial pathogenesis and antibiotic resistance.

We plan to use a systems biology approach, conducting genotypic and phenotypic analyses of a broad spectrum of critical bacterial pathogens, thereby offering a comprehensive and in-depth understanding of the complex interplay between host bacteria, plasmids and resistance genes.

Furthermore, we aim to uncover the role of small cryptic plasmids in the dissemination of antibiotic resistance within bacterial populations.

Our detailed understanding on PCN control could aid in the design of innovative treatment strategies that mitigate resistance development.